Chapter 56: The Chronic Lymphocytic Leukemias

DEFINITION

• Chronic lymphocytic leukemia (CLL) is a neoplastic disease characterized by accumulation of small, mature-appearing lymphocytes in blood, marrow, and lymphoid tissues.

• The most prevalent adult leukemia in western societies.

• The age-adjusted incidence rate for CLL in the United States is 4.2/100,000 persons according to the Surveillance Epidemiology and End-Result Program of the National Cancer Institute.

• The age-adjusted incidence rate of CLL worldwide is 2.5/100,000 persons as determined by the International Agency for Research on Cancer of the World Health Organization.

• In 98 percent of patients, the disease is of B-cell lineage; less than 2 percent of patients have T-cell lineage leukemia.

• Approximately 0.8 percent of all cancers and approximately 30 percent of all leukemias annually.

• CLL is very uncommon in Eastern Asia (e.g., Japan and Korea).

ETIOLOGY AND PATHOGENESIS

Environmental Factors

• There is no exogenous factor (e.g., chemical, solvent) that has been established to increase the risk of CLL.

• Radiation exposure both in the Japanese as a result of the atomic bomb detonations in World War II and in Western cultures in patients treated with radiation for spondylitis and uterine cancers did not show an increased risk of CLL, despite an increased incidence of the acute leukemias and chronic myelogenous leukemia.

• CLL B cells may have receptors for Epstein-Barr virus but are not subject to EBV infection.

Hereditary Factors

• Familial occurrence in some patients.

  — Multiple cases of this leukemia may be found within a single family.

  — May also be found in association with other indolent lymphoproliferative disorders.

  — First-degree relatives of patients with lymphoplasmacytic lymphoma or Waldenström macroglobulinemia (see Chap. 70) have a greater than threefold risk of developing CLL.

• Genetic factors that contribute to increased incidence of CLL:

  — Early studies have associated the risk of developing aggressive CLL with polymorphisms in the gene encoding CD5 (located at 11q13), CD38 (located at 4p15), or tumor necrosis factor-α (TNF-α) and other genes mapping to 13q21.33-q22.2.

  — Disease-susceptibility associated with single nucleotide polymorphisms in or around genes encoding proteins involved in apoptosis or immune regulatory pathways, namely CCNH (located at 5q13.3), APAF1 (located at 12q23), IL16 (located at 15q26.3), CASP8 (located at 2q33.1), NOS2A (located at 17q11.1), and CCR7 (located at 17q21.2).

Immunoglobulin Expression

• The leukemic cells from over 90 percent of patients with CLL express low levels of monoclonal surface immunoglobulin.

• Sixty percent of patients cells express κ light chains and 40 percent with λ light chains.

• Evidence for selection in the immunoglobulin genes expressed by CLL argues that stimulation through the immunoglobulin receptor plays a role in leukemogenesis.

• CLL cells express IgM in 25 percent and both IgM and IgD in over 55 percent of cases and rarely express other immunoglobulin isotypes.

Monoclonal B-Cell Lymphocytosis

• Studies using flow cytometry have ...